Inflammation has been argued to play a primary role in the pathogenesis of Alzheimer's disease by contributing to the development of neuropathology and clinical symptoms. However, the mechanisms underlying these effects remain obscure. Lipopolysaccharide (LPS) activates the innate immune response and triggers gliosis when injected into the central nervous system. In the studies described in the present work, we evaluated the time course of microgliosis after a single intrahippocampal injection of LPS. Mice were injected bilaterally with 4 μg of LPS. Post-injection survival times were 1, 6, and 24 h, as well as 3, 7, 14, and 28 days. Protein and RNA analyses were performed for inflammatory markers. Significant elevations of cluster differentiation marker CD45, glial fibrillary acidic protein (GFAP), scavenger receptor A (SRA), and Fcγ receptor mRNA were seen after 24 h. Immunohistochemistry revealed a complex pattern of protein expression by microglia, as well as changes in cell morphologies. RNA and protein for Fcγ receptor and SRA were transiently elevated, peaked at 3 days, and returned to basal levels after 1 week. In contrast, microglia remained significantly activated through the 28-day time point, as determined by CD45 and complement receptor 3 levels. These findings indicate a multivariate response to LPS, and evaluation of microglial phenotypes may lead to a better understanding of neuroinflammatory diseases. © 2005 Wiley-Liss, Inc.